The biochemical mechanism of cocaine-induced hepatic necrosis will be investigated. Cocaine produced a species-dependant periportal necrosis of the liver in animals pretreated with known inducers of microsomal drug metabolism activity. This effect appears to be related to be metabolism of cocaine by microsomal enzymes in addition to the previously reported inactivation by esterases. Enhancement of microsomal enzyme actively alters cocaine toxicity to decrease catecholamine related deaths but produces a delayed letahlity related to hepatic damage. The biotransformation of cocaine will be studied in animals following pretreatment with agents which alter microsomal drug metabolism. Further studies will examine the biochemical mechanisms involved in the production of cocaine-induced hepatic necrosis as well as observed species dependance of the necrosis. These studies will include the role of glutathione in formation of the necrosis and of the initial cellular organelles involved in the cocaine-induced lesions. Studies on the effects of pretreatment with other commonly abused substances on cocaine toxicity will provide significant information toward understanding the toxic effect of cocaine abuse in man. The objectives of these studies will be to evaluate the toxicological significance of cocaine-induced hepatic necrosis.